TW201103547A - 17β-alkyl-17α-oxy-oestratrienes - Google Patents

Abstract

The invention relates to 17 β-alkyl-17α -oxy-oestratrienes of the formula (I), to processes for their preparation, to the use of the 17 β-alkyl-17α -oxy-oestratrienes for preparing pharmaceuticals and to pharmaceutical preparations comprising these compounds.

Description

201103547 VI. Description of the Invention: [Technical Field] The present invention relates to a 17β-alkyl-17α-oxy-estramid, a preparation method thereof, and 17β-alkyl-17α-oxy-estramidine The olefin is used in the preparation of a drug and a pharmaceutical preparation comprising the same. [Prior Art] The compounds according to the present invention have an antiestrogenic effect, i.e., such substances can inhibit estrogen. These substances have been extensively described. For example, a compound having an anti-hormonal effect is known as Ερ 0138 504 Β1. These substances are essentially _13,5 〇〇)triene derivatives which are substituted at the 3-position, in particular by hydroxyl or alkoxy groups, via a base group at the 17α_ position and especially hydrogen at the 17β-position. Or alkyl substitution. In addition, these compounds have a pendant base group at the 7α-position which may be partially moalized and which may interdigitate interstitially with amidino, amine, amine oxime-oxide, oxy, thiol, sulfin Sulfhydryl and/or sulfonyl. WO 99/33855 Α 1 describes an ΐΐβ-halo-7α-substituted female 甾 1 '3,5( 10)-diluted </ /> which may have a hydroxyl group at the 3_ and 17-positions. The 7α-side chain is partially unsaturated and requires an unsaturated hydrocarbon chain interspersed with an amine nitrogen atom or a sulfur-burning group, a sub-branched base or a continuation base. Other compounds are described in WO 98/07740 Α1. These are substituted 7α-(ξ-aminoalkyl)anthracene, 3,5(1〇)-triene. At the 3 position, these compounds preferably have a hydroxyl group, a methoxy group or an ethenyloxy group, and preferably have a methyl group or a trifluoromethyl group at the 17{3_ and/or 17α-position. Preferably, the lip_ position is occupied by a fluorine atom and the 7α-position is preferably occupied by an alkyl side chain, and the terminal of the alkyl side chain 148586.doc 201103547 is at least partially fluorinated with an amine nitrogen atom and sulfur interposed therebetween. Alkyl, sulfinyl or sulfonyl. WO 97/45441 A1 discloses a 7〇1_(5-decylaminopentyl) esculine-1,3,5(10)-triene having a hydroxyl group at the 3_position and the 17α-position. The position can be occupied by a thiol or ethynyl group. Further, the position of the leucotriene skeleton may be substituted by a fluorine atom. It has been found that known compounds form various biologically highly active metabolites upon administration. The formation of such metabolites can lead to undesired effects and thus to an uncontrolled spectrum of activity. Special words; "There may be side effects, or the main role required (antiestrogenic effects) becomes uncontrollable due to spontaneous formation. Furthermore, it is known that compounds are not satisfactory when administered orally. In particular, it has been found that known compounds can promote the accumulation of alveolar macrophages. None of the prior art antiestrogens have satisfactory oral bioavailability. In addition, prior art antiestrogens interact with cytochrome puroxidase. The structurally closest prior art forms a compound of WO 03/045972 which differs from the compound according to the invention in that it is uninvited at position 17 and has a high yield ^ (4) wind group not attached at the α-position, and The oxygen-containing group bonded at the position and bonded to the position 17 is not attached to the β-position of the female frame and is at the α_ position. To date, the prior art has deviated from 17ρ alkyl·ΐ7α_oxy-estramid: because there are a large number of indications that these compounds are not to the estrogen receptor; there is still affinity, and therefore the estrogen is expected Or anti-estrogen strokes ^ 1979, 22 (12), 15 s). Even if you are familiar with this technology (148586.doc 201103547 does not consider this point], it still faces the problem of finding the synthetic path of 17β_alkyl_17α_oxy_estrylene, because the prior art only elaborates complex and hardly Promising Paths. Based on this prior art, it is an object of the present invention to provide other antiestrogenic compounds which form very little, if any, biologically active metabolites. Furthermore, the compounds studied are administered orally. There should be improved bioavailability' thereby reducing patient stress. This can increase patient compliance. Surprisingly and without consideration of the foresight of those skilled in the art, it has been found that 17[beta]-alkyl-17[alpha]-oxygen according to the present invention has been found. The basal-estretriene has antiestrogenic properties and a greatly improved bioavailability. This is not expected. SUMMARY OF THE INVENTION One object of the present invention is to use a 17th alkyl group of the formula (1). - the salt of the female tri-enriched and its enantiomers and diastereomers' salts, solvates and solvates,

among them

Hal represents Dun or chlorine, which is attached to the 丄i β_ position of the genus triadene skeleton; and R: 'R2 and R4 systems, independently of each other, represent hydrogen, fluorine, gas or desert, and R3 卩 hydrogen Or ci_c4-homogeneous or Cl_C4_burning thiol, and 148586.doc 201103547 R17 represents hydrogen or C1-C4-alkyl or C^-C^t-homolinyl,

Rl7&quot; represents 单- or polyfluorinated 匚丨-匚^alkyl, C2-C4-alkenyl or C2-C4-alkynyl as desired, wherein R17-0 and R17 are at 17α-position and 17β-, respectively. Position attached to the ezetylene skeleton; and U represents a linear or branched CVCn-alkylene group, a C:2-C13-extended alkenyl group or a C2-C13-extension group, or a group A_B, wherein A is attached to the estradiol backbone and attached to the benzylidene group via _Ch2_, phenyl or attached to the estroxene via an alkyl group. a phenyl group, and a B chain linear or branched chain ^^^-alkyl, C2-C13-alkenyl or C2-C13-exetylene, and wherein A and B may also be attached to each other via an oxygen atom And V represents a fluorenylene or -C(O)- group and X represents a bond or (^-(: 3-alkyl and r5 represents hydrogen or Ci-Cr alkyl, C2-C4-alkenyl or c2) -c4-alkynyl R6 represents hydrogen or a group -CHrR7 or C(0)-R7, wherein R7 represents hydrogen or a straight or branched chain non-fluorinated or at least partially fluorinated Ci_c6_alkyl, CVC6. CVC6-fast radical, which may be substituted by a mono- or poly-substituent, or R and R6 together with the nitrogen atom of X and a side chain to form a 4- or 6-membered heterocyclic group a ring which may have other heteroatoms in addition to the nitrogen atom of the side chain and/or may contain a carbonyl group, 1485S6.doc 201103547 γ represents a c5-c8-alkylene group, and E represents a C1-C4-perfluorocarbon group or represents a halogen. Or -CF3% - to pentasubstituted phenyl. This application is based on the following definitions:

Cn-burning base:

The Cn-alkyl group represents a linear or branched bond saturated monovalent hydrocarbon group having n carbon atoms.

Cn-alkylene:

The Cn-alkylene group represents a linear or branched saturated divalent hydrocarbon group having n carbon atoms. CV-extended alkenyl group: The cn-extended alkenyl group represents a linear or branched-chain divalent hydrocarbon group having η carbon atoms and at least one double bond.

Cn-exetylene group: The cn-exetylene group represents a linear or branched branched divalent hydrocarbon group having η carbon atoms and at least one triple bond.

Cn-alkenyl:

The Cn-alkenyl group represents a linear or branched chain monovalent hydrocarbon group having n carbon atoms and at least one double bond.

Cn-fast radical: The cn-alkynyl group represents a linear or branched bond monovalent nicotine group containing n hindering atoms and at least one triple bond. Cn-Alkylcarbonyl = cn-alkyl fluorenyl: cn-alkylcarbonyl represents a group -C(0)-Cn-alkyl. 148586.doc 201103547 ° _ 1 to 6 ' is preferably 1 to 4 and particularly preferably 1 to 3. The following groups may be mentioned by way of example or in a preferred manner. Heteroatoms: It should be understood that a hetero atom means an oxygen, nitrogen or sulfur atom. Heteroaryl Heteroaryl systems contain at least one indole or bicyclic ring system. May exist after the worker / hetero atom is a nitrogen atom, an oxygen atom and / or furnace: the 'price can be located in any aromatic carbonogen - heterocyclic group for the purposes of the present invention, the hetero-based system is completely or a partially hydrogenated heteroaryl group (a heteroatom-saturated heterocyclic group of a fully hydrogenated heteroaryl A b ), that is, a non-atom having a hetero atom or a hetero atom to +: + is a nitrogen atom, Or a sulfur atom two; 4 on any stone anatomical atom or nitrogen atom. Becker = the monocyclic heterocyclic ring of the present invention may have (four) ring atoms. The base of the ... includes, for example, a nitrogen heterocycle Ding has 5 ring atoms (5 members)

Spider... % of clothing base includes (for example). The phenanthroline A + azole "mercapto group, pyrazolidine group and pyrroline group. The heterocyclic ring having 6 ring atoms includes, for example, piperidinyl, morpholinyl and thiomorpholinyl. A. Piperazine Halogen The term dentate includes fluorine, gas, bromine and iodine. 148586.doc 201103547 It is preferred to use fluorine. In the general formula (1), Hal represents a chlorine or a chlorine which is attached to the ?-position of the frame. Preferably, Hal represents a fluorine atom. In the pass _ bromine. More than 'R1' Ri R4 stand independently of each other for hydrogen, chlorine or desert. Particularly preferably, R1 represents argon, R2 represents hydrogen or chlorine and R4 represents hydrogen, chlorine or bromine. Most preferably, R1, R2 and R3 represent hydrogen. In the formula (1), R; represents hydrogen or a sulfonium group. The butyl group preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl or tert-butyl or the corresponding alkyl fluorenyl (ethenyl, propyl, butyl). Particularly preferably 'R3 stands for hydrogen or methyl or ethylidene. Most preferably 'R3 stands for hydrogen. In the formula (I), R5 may represent hydrogen or a Ci_C4_alkyl group, a C2_C4 alkenyl group or a C2-C4. fast group e R5 preferably represents hydrogen or a Ci_c3_alkyl group. R5 is particularly preferred for hydrogen. In the formula (1), R6 may represent hydrogen or a group -CH2-R7 or C(0)-R7, wherein R represents chlorine or a straight or branched chain non-fluorinated or at least partially fluorinated Ci_C6 alkyl group, CpC: 6-alkenyl or C2_C6-alkynyl, which may be mono- or polysubstituted by hydroxy, or 148586.doc 201103547 preferably represents nitrogen or -CHyR7, wherein R7 specifically represents hydrogen or methyl or ethyl. R6 is particularly good for 曱基. In the general formula (1), 'r5&amp;r6 may form a 4- to 6-membered heteronuclear ring together with the nitrogen atom of X and the side chain, which may have other hetero atoms other than the nitrogen atom of the side chain and/or may contain a carbonyl group. Preferably, the ruthenium 6 and the ruthenium 6 may have a heteronuclear ring in addition to the nitrogen atom of the side chain and may contain a carbonyl group. R5 and R6 are particularly preferred to form a pi-bipyridyl ring together with the nitrogen atom of the side chain. In the general formula (1), 'R' may represent hydrogen or CVC4-alkyl or CVC4-alkylindenyl. In the formula (1), R17'· may represent a mono- or polyfluorinated Ci_C4_----c2 -c4-alkenyl or c2-c4-alkynyl. τ&gt; 1 7, 〇 and R are attached to the equinone skeleton at the 17α-position and the 17β-position, respectively, in particular, the ruler and the ruler 7&quot; is methyl, ethyl, n-propyl, isopropyl, n-butyl 'isobutyl and tert-butyl.

Further preferably, Rl7 is hydrogen, ethyl hydrazino, propyl fluorenyl and butyl fluorenyl. Further preferably, ethynyl, 1-propynyl, 2-propynyl, 丨-butynyl, 2-butynyl and 3-butynyl, and trifluoromethyl, pentafluoroethyl, and Fluoropropyl and nonafluorobutyl. R17' particularly preferably represents hydrogen, methyl or ethyl fluorenyl. R17'' particularly preferably represents an anthracenyl group, an ethynyl group or a trifluoromethyl group. R17 best represents hydrogen. R17 best represents methyl. I48586.doc 10 201103547 In the general formula (1), u represents a straight or branched chain Ci_Ci3_alkylene, a cn-alkenyl or CVCn-alkynyl, or represents a group AB, which is attached to The estradiol is on the skeleton and is via a sub-f group attached to the estradiol, and the phenyl group or the Ci-C3-alkyl-extension attached to the esculent via the leuco group Phenyl, and B is a straight or branched chain Ci_Cn_(tetra)yl, Μ&quot;•enkenyl or c” Ci3-exetylene, and wherein A and B may also be attached to each other via an oxygen atom, ϋspecifically straight Chain or branched chain alkyl group. Methylene, ethyl, propyl, butyl, hexyl, hexyl, octyl, decyl, decyl, undecane It is preferred that the base, the dodecyl group or the thirteen alkyl group. Particularly preferably 'U represents _(CH2)p_, wherein ρ is an integer of 2 to 1 。. Particularly preferably, the U is a butyl group and a butyl group. Preferably, the U system is a butyl group, that is, for the formula -(CH2)p-, U, p=4. In the formula (I), V represents an anthracene group or c. (〇) group. V specific statement stands for Aachen. Therefore, in an optimal In the embodiment, the group UV may be a n-pentyl group. In the formula (I), X represents a bond alkyl group. Preferably, an X bond or a methylene group. Particularly preferably, the X bond is in the formula In (1), Y represents a C5-C8-alkylene group. Preferably, a 'Y-bond or a c5-c7-alkylene group. 148586.doc • 11 - 201103547 Particularly preferably, the Y-system is a pentyl group or a hexanyl group. In the formula (1), 'E stands for Ci_C4_perfluoroalkyl group or represents a phenyl group or a mono- to penta-substituted phenyl group. = Preferably represents -CF3, -C2F5, -C3F7, _c4F9, representing dentate and/or two. Fluoromethyl mono- to trisubstituted phenyl. E particularly preferably represents -C2F5, _C3F7, 9 or represents tri-decylphenyl. E best represents _c2F5. A preferred subgroup of compounds is a compound of formula (1) and a salt of an enantiomer and a diastereomer thereof, a salt, a solvate thereof and a solvate thereof, wherein Hal represents fluorine, and R3 R5 R6 R1, R2 and R4 independently of each other represent hydrogen, gas or bromine And representing hydrazine, methyl or ethyl hydrazino, and representing hydrogen or Ci-C3-alkyl, and representing hydrogen or -CH2-R7, wherein JL is represented by hydrogen or methyl or ethyl, or with a side chain Nitrogen atom 5 heterocyclic ring which in addition to the side chain atoms of the gas may have other hetero atom and / or may contain a carbonyl group, and

RRUVX represents hydrogen, methyl or ethylidene, and represents methyl, ethynyl or trifluoromethyl, and represents a butyl group, a pentyl group or a heptyl group, and a methylene group, and Represents a bond or methylene group, and 148586.doc •12·201103547 represents a bond or c5-c7-alkylene group, and E represents -C2F5, -C3F7, -C4F9* represents a trifluoromethylphenyl group. The preferred subgroup of compounds is formed from the compound of formula (1) and its enantiomers and diastereomers, salts, solvates and solvates thereof, wherein R represents hydrogen and r2 represents hydrogen or gas. And r4 represents hydrogen, chlorine or bromine, and r3 represents hydrogen, and

Hal R5 R5 and R6 R17' R17,. U V X represents fluorine, and represents hydrogen and R6 represents a sulfhydryl group, or is formed together with a nitrogen atom of a side chain. Than each bite ring, and represent hydrogen, and represent a thiol group, and represent a butyl group, and represent a fluorenylene group, and a representative bond, and γ represents a pentylene group or a hexanyl group, and Ε represents a -c2f5. The pharmaceutically acceptable acid addition salts and esters of 17β-alkyl-17α-oxy-estrene are also encompassed according to the invention. This addition salt is a corresponding salt formed with an inorganic or organic acid. Suitable addition salts are, in particular, the hydrochloride, hydrobromide, acetate, citrate, oxalate, tartrate and sulfonate. If R3 and R17' are hydrogen, that is, 3,17?-diol is present, an ester of such a hydroxy compound can also be formed. Preferably, such esters are formed with a mineral acid which is the same as the acid used in the 148586.doc 13-201103547 addition salt formulation, i.e. specifically acetic acid, but may be a higher carboxylic acid, such as (for example) propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid or pivalic acid. The novel 17(3-alkyl-17α-oxy-estretriene has a plurality of pairs of palmitic centers. Thus, in each case, there are a plurality of stereoisomeric forms of each compound. The compounds of formula I can Isomers, stereoisomers or geometric isomers are present. In addition, the invention also covers all possible isomers, such as the purine and purine isomers, the S and R enantiomers 'diastereomers Constructs, racemates, and mixtures thereof (including tautomeric compounds, all such isomer compounds, even if not explicitly stated) form part of the subject matter of the present invention. Known methods (such as scrubbing, chromatography or salt formation) are separated into enantiomers or £/2 isomers. Particularly suitable for the purposes of the present invention are compounds having the general formula , ie, -11, fluoro, fluoro, phenyl, phenyl, phenyl, phenyl -triene-3,17α-diol-Ηβ·fluoro-17β-mercapto-7-[5-[(2R)-2-(7,7,8,8,8-pentafluorooctyl)-b °Byrridinyl]pentyl]estrone-1,3,5(10)-triene-3,17〇1- Alcohol-nP_fluoro-17P-mercapto-7-[5-[(2R)-2-(6,6,7,7,7-pentafluoroheptylfluorenyl)pentyl]-errone-1 3,5(10)-triene-3,17α-diol-4-chloro-UP-fluoro-17Ρ-methyl-7-[5-[mercapto (8,8,9,9,9_5 Fluorinyl)amino]pentyl]estrone-1,3,5(10)-triene-3,17α-diol-4-bromo-11β-fluoro-17β-methyl_7_[5-[ Mercapto (8,8,9,9,9-pentafluoroindenyl)amino]pentyl]estrone-1,3,5(10)·triene-3,17α-diol 148586.doc • 14 - 201103547 4-Bromo-11β-fluoro-17β-mercapto-7-[5-[(2R)-2-(7,7,8,8,8-pentafluorooctyl)-1-pyrrolidinyl ] amyl] female _1,3,5(1〇)_triene_3,17α-diol-4_ gas-11β_fluoro-17β-mercapto-7-[5-[(2R)-2- (7,7,8,8,8-pentafluorooctyl)-1-pyrrolidinyl]pentyl]estretriene_3,17αdiol_ 4_ bromo-UP·fluoro_17β-fluorenyl_7 -[5-[(2R)-2-(6,6,7,7,7-pentafluoroheptyl)-1-0 ratio. Stationary] amyl] female Cui, 3,5 (ι〇)_ Tris- 3, ΐ7α-diol-4_ chloro-Ηβ-fluoro·17β-methyl-7-[5-[(211)-2-(6,6,7,7,7-pentafluoroheptyl) -1-pyrrolidyl]pentyl]estretrienyl-3,17α-diol-2,4-dioxa-11β-fluoro-17β-mercapto-7-[5-[(2R)-2 -(7,7,8,8,8-pentafluorooctyl -1-pyrrolidinyl]pentyl]estrogen, succinyl-yl-terodiol diol according to the invention 17β-hospital-17α-oxy-estrene trisin differs from known compounds Also in the position where the tooth atom system is attached to the 丨丨β-position and the alkyl group is attached to the 17β-position. The 17β-alkyl-17α-oxy-estretriene of the present invention does not substantially form a metabolite as compared with the unsubstituted 3 at the 17β-position, ΐ7α-dihydroxy-estramid. Metabolites can also be biologically active. It has been found that the estrene derivative formed by oxidation of a hydroxyl group attached at the 17α position, which produces an i 7 _ pendant oxy derivative, has extremely strong biological activity. This oxidation reaction can be prevented by blocking the 17p_ position with an alkyl group (specifically, Cl_C4_alkyl group) which also inhibits the metabolic species. The estriol according to the invention for use as an active compound therefore has non-species-dependent potency and activity. Thus, the advantage of such compounds is that the overall potency of the active compound is achieved in a single compound. Therefore, there is an advantage in the development of drugs 'because of the lack of formation of organisms I48586.doc 15 201103547 active metabolites' which tend to attribute efficacy to certain structures and thus to more objectively study the active compounds. Further, according to the present invention, ?17Pn17a_oxy_estretriene can inhibit the action of estramethylene by almost 100%. Therefore, it is anti-estrogen. To test the efficacy of the compounds according to the invention, in vivo tests were performed with neonatal rats. 4 This drug was administered orally (p.) to detect uterine growth (testing for antiestrogenic effects). The principle of this method is to investigate the effect of administering an antiestrogenic compound while administering estrogen. In rodents, administration of estrogen causes an increase in uterine weight (due to proliferation and water retention). The peak length can be inhibited in a dose-dependent manner by simultaneously administering a compound having an antiestrogenic effect. For this test, newborn females weighing 35-45 g were carefully examined at the beginning of the trial. Five to six animals were tested per dose. For oral administration, the substance was dissolved in one part of ethanol (E) and filled with nine parts of peanut oil (p(7). To adapt to the environment, the young rats born from the mother rats were distributed to the day before the start of treatment. Cage and feed immediately. The animals were then treated once daily with 〇5肫 diol benzoate (EB) for three days. eb__ was administered subcutaneously (sc), and the test substance was After the last administration of μ hours, the oral technique was weighed and killed, and the uterus was removed. The moisture weight of the prepared uterus was determined (less content was performed in the following control study. For the negative control, each Animals were administered a mixture of 〇2 ^ Ε/ρ〇 daily. For positive control studies, 'Every animal was administered 〇$ ΕΒ/0·1 ml per day 〇148586.doc •16· 201103547 For each group, The mean value of the relative organ weight (mg/HH) g body weight in the Dunnett test was significantly different from the standard deviation (x ± sd) and the control group (eb) (p &lt; 〇. 〇 5) 〇 using the leaf calculation program The inhibition rate (in %) relative to the control group was determined. The relative potency of the test substances was calculated by covariance and regression analysis. The test results of the selected compounds are shown in the table. The results showed that 0.5 pg EB/0.1 mi and 0 03 mg/kg body weight were administered subcutaneously. The test results of the rat uterus growth by oral administration of a compound having an estrogenic effect.

As can be seen from Table 1, if the dose of about 0 03 mg/kg is orally administered, the antiestrogenic effect is 50%. The compounds according to the invention are effective or even more effective than those which are not substituted at the 17β• position. The etotriene according to the present invention also has better compatibility than the compound which is not substituted at 17 M stand, so that the latter is preferred. Better compatibility is specifically attributed to the substantial restriction of the formation of metabolites. Furthermore, the compounds according to the invention are characterized by an extremely high bioavailability' and thus a high sputum concentration can be achieved in the patients studied by administering a compound according to the invention. The high compatibility combination already mentioned by Xiao, which may be successfully and safely treated, as the compound according to the invention can be used to determine an activity that is completely different from the effective concentration of the compound under study. Serum concentration of the compound. The effective concentration is the minimum active compound plasma concentration required to achieve the desired effect in an individual indication. The 17β-alkyl-17α-oxy-estrylene triene of the formula 1 according to the present invention is particularly suitable for the preparation of a medicament. Accordingly, the present invention is also directed to a pharmaceutical preparation comprising at least one pharmaceutically acceptable carrier, in addition to 17ββ-hospital-17α-oxy-estramidine of formula 1. The pharmaceutical preparations or compositions according to the invention are prepared in a manner known per se using conventional solid or liquid carriers or diluents suitable for the desired dosage form, as well as conventional pharmaceutical and industrial auxiliaries. A preferred formulation consists of a dosage form suitable for oral, enteral or parenteral administration (e.g., LP. (intraperitoneal), i.v. (intravenous), i.m. (intramuscular) or transdermal). Such dosage forms are, for example, tablets, film lozenges, coating agents, tablets, capsules, powders, creams, ointments, lotions, liquids (such as syrups), gels, injectable liquids (for example, In i, P., iv, im or percutaneous injection). In addition, the storage form (such as implantation and &amp; _ is also suitable. In this case, the individual preparations will be released into the body according to their type according to the type of female g of sputum gradually or in a short time. For administration, capsules, tablets, troches, coated troches and liquids or their known known oral administration forms can be used as pharmaceutical preparations. In this case, the drug can be formulated to release the active compound in a short time. And delivered to the individual, or have a staging effect to achieve a more durable, slow supply of vomiting. The individual to the individual. In addition to at least _ kind of leucotriene, the dosage unit can be packaged 148586.doc 201103547 including one or more medicines Compatible carrier 戟μ (such as used to adjust the rheology of the drug), surfactants, do, cross-linking such as β, mixture, microcapsules, particles, particles, dilution 刎, adhesive (such as Starch, sugar, sorbitol and gelatin), and fillers (such as citric acid and talc), assisted, q-etched, colorants, perfumes and other substances 相应0 corresponding bonds can be made, for example, by active compounds Known with Lai Inert diluents (such as dextrose, tang, sorbitol, mannitol, polyvinylpyrrolidone), degumming agents (such as corn starch or alginic acid), binders (such as starch or gelatin), slippery It is known that a mixture of such agents (such as a slow-radical polymethylene group, a methylidene fiber/alkaline phthalate or a polyvinyl acetate) is mixed. The tablets may also be composed of a plurality of layers. Coating a core similar to a tablet by using a reagent commonly used in coatings for coated tablets (such as polyethylene ketamine or shellac, gum arabic (gum, talc, titanium oxide or sugar) Here, the outer casing of the coating agent may also be composed of a plurality of layers, wherein the above-mentioned auxiliary agent for the tablet may be used. The capsule containing the active compound may, for example, be such that the active compound and the inert substance are inert. The carrier (such as lactose or sorbitol) is mixed and encapsulated in a gelatin capsule. The esculetin according to the present invention may also be formulated into a solution intended to be orally administered, in addition to the active estriene. In addition, it also contains pharmaceutically compatible oils and/or pharmaceuticals. a lipophilic surfactant and/or a pharmaceutically compatible hydrophilic surfactant and/or a pharmaceutically compatible water-miscible solvent as a component. 148586.doc -19- 201103547 The compounds of the present invention may be formulated into cyclodextrin chlatrate for better bioavailability of the active compounds of the invention. For this purpose, the compounds are reacted with α_, β- or γ-cyclodextrin or a derivative thereof. To use externally applied creams, ointments, lotions and liquids, they must be formulated such that the compound according to the invention is provided to the individual in sufficient amounts. Such dosage forms comprise adjuvants, for example for regulating drug flow. Denatured substances, surfactants, preservatives, solubilizers, diluents, substances, coloring agents, perfumes and skin protectants (such as conditioning agents and moisturizing agents) for increasing the permeability of the estrentin according to the present invention to the skin. And the compound according to the invention, the medicament may also comprise other active compounds (UUmanns Enzyklopadie der technischen Chemie [Ullmann's Encyclopedia of industrial chemistry], Volume 4 (1 953), pp. 1-39; j Pharm. Sci., 52, 918 ff. (1963); H. v.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete [Auxiliaries for pharmacy and related fields] ; Pharm. Ind ., 2, 72 ff (1961) ; Dr. Η. P. Fiedler, Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of auxiliaries for pharmacy, cosmetics and related fields], Cantor AG, Aulendorf/WUrtt., 1971 ). The substances according to the invention may also be used in a suitable solution, such as, for example, physiological saline, as a solution for infusion and injection. For parenteral administration, the active compound can be dissolved or suspended in a physiologically compatible diluent. In particular, suitable diluents are oily solutions such as, for example, solutions containing sesame oil, castor oil and cottonseed oil. To increase the solubility, a solubilizing agent such as, for example, benzyl pentate or benzofuran may be added to 148586.doc -20, 201103547. For the formulation of injectable (four)' any liquid carrier can be used and the compound according to the invention can be transferred or chopped. These (4) usually also contain substances for adjusting the viscosity, surfactants, preservatives, solubilizers, diluents and other additives for the preparation of isotonic baths. Other active compounds can also be administered in conjunction with estradiol. The W dilute according to the present invention may also be administered in the form of an injectable solution or an implant preparation (e.g., subcutaneously). Such formulations may be formulated such that the active compound will be delayed in release. To this end, known techniques can be used, such as deposits that are cold worked or manipulated through the membrane. With regard to inert materials, the implant may also have, for example, a biodegradable polymer or a synthetic polyoxo, such as a polyoxygenated gum. For transdermal administration, it is also possible to incorporate estriol (such as a patch. The article according to the present invention can also be used in the skin of a skin for administration. ' :&amp; · i produces a therapeutically effective concentration of ▲ liquid, and may also be used in a human skin system according to a similar description of other anti-estrogens in WO 01/76608. These skin-penetrating systems are characterized by The ratio of two penetrants (specifically lauric acid to propylene glycol). The dosage of the substance of formula I of Kangben Qiming is determined by the attending physician and in particular, depending on the substance administered, the method of administration, and the condition to be treated. The disease and the severity of the disease I. The amount of the compound to be administered can be varied within a wide range to cover any effective amount. Depending on the condition to be treated and the type of administration, the amount of the S substance can be 0. 02~20 mg/kg body weight/day, preferably 148586.doc 201103547 〇·1 1 mg/kg body weight/day. In humans, this is equivalent to the daily dose of ( (10) 〇. The preferred dose of sputum for humans is 5_5〇mg. This is especially suitable for tumor treatment. This dose can be administered in a single dose Formulated with or divided into two or more doses. Compounds of formula I are compounds that have potent antiestrogenic activity. These compounds are useful in the treatment of estrogen-dependent diseases such as breast cancer (tamoxifen) (tamGxifen) second-line treatment of breast cancer; used to replace tamoxifen to assist in the treatment of breast cancer), endometrial cancer, nest cancer, benign prostatic hyperplasia, anovulatory infertility and melanoma. Progestogens (competitive progesterone antagonists) are used together to treat hormone-dependent tumors (EP 3 1 〇 542 A). The compounds of formula I may also be combined with other active compounds having anti-proliferative effects. Combinations of inhibitors such as anastrozole, letrozole or exemestane are preferred. Other indications of compounds of formula I can be used for hair loss and sloppyness in men. Sexual alopecia 'alopecia and hirsutism caused by chemotherapy (Hye_Sun 〇h and

Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996) 12525-12530). Furthermore, the compounds of formula I are useful in the preparation of medicaments for the treatment of gynecological diseases such as endometriosis. For gynecological diseases, the compounds according to the invention may also be combined with progestin and/or estrogen. For example, 'the general formula' can be used as a component of the product described in particular in EP 346 014 B1, which products include estrogens and pure anti-hormone and are intended to be used simultaneously, sequentially or separately for near menopause or 148586. .doc -22- 201103547 Selective estrogen therapy for women after menopause. In addition, the compounds of formula I are useful in the preparation of pharmaceutical compositions for male and female fertility control (male fertility control: DE 195 1086 2.0 A). [Embodiment] The estradiol triene according to the present invention can be prepared according to a method similar to the known process:

17-epi-methylchlorodio! 17-epl-PFE*methyldlol Scheme 1 Scheme 1 shows the reaction scheme in which the compounds according to the invention can be prepared.

In principle, all of the listed compounds can be prepared from the 17-side oxy compound. The preparation of the 17-side oxy compound is illustrated by way of example in WO 99/33855 [CAS: 204138-84-1 (Cl-on, 2b), CAS: 204138-92-1 (Br-on, Lg), CAS: 204138-93-2 (Br-ol)]. Other derivatives having the same substitution pattern other than the compounds explicitly disclosed in this document can be similarly prepared. The estradiol triene according to the present invention can also be produced from the 17α-hydroxy or 17α-alkoxy compound ("17α-ΟΗ") in the same manner. The production of such derivatives is also described, for example, in WO 148586.doc • 23 2011032547 99/33855. This document also discloses, in the same manner, a process for the 17α-trans group or the 17α-alkoxy compound and the 17-side oxy compound having an amine group in the side chain of the 7α_ position. If the preparation of the starting materials is not illustrated, the starting materials are known or commercially available or the compounds are synthesized analogously to the process. The preparation of certain precursors, intermediates, and products is illustrated below by way of example. For the preparation of the substances according to the invention, for example, the following process is used (see also ΕΡ 0138 504 Bl; WO 97/45441 Al; WO 98/07740 Α 1 ; WO 99/33855 Α 1): side chains at the 7α-position It can be constructed by, for example, the program described in w〇98/07740 Α1. In the process steps described below, the groups R丨, R2, R3, R4, R5, 116, "^1, 1117', 1117'', 1;, ¥, 乂, 丫, ugly have the above definitions. P G represents a protecting group such as an ether, an ester or a carbonate. It is particularly preferable to use a base or a sulfonyl ether, and it is preferred to use a butyl decyl decyl group and a tetrahydropyranyl ether. LG stands for a leaving group such as a sulfonate group or a yl group. It is particularly preferred to use an benzenesulfonate or oxime sulfonate group and a gas, bromine or iodine group. It is preferred to use a gas or a methanesulfonic acid S. R2G represents hydrogen or, if desired, mono- or polyfluorinated q-Cr alkyl, c2-c3-alkenyl or c2-c3-alkynyl. In the process step a) as required, the 3-hydroxy---substituted 3-hydroxyestrone-17-one of the formula III (WO 99/33855) 3-hydroxy is supported by decane The catalyzed reagent or dihydropyran is reacted to convert, for example, a compound of the formula IV to 148586.doc -24 to 201103547 (d) (d) or tetrahydropyranyl (iv). The reaction is carried out for 3 hours at room temperature (0-100. in a #protic solvent (eg, dichloromethane) in the presence of an assay (eg, hydrazine) or an acid (eg, quinone benzoic acid d ratio (iv)). Time (1 to 24 hours).

Alternatively, process step a) is carried out according to (Dw Hansen and D piHpauskas J. Org. Chem. (1985) 945*KF Bernady et al. 〇rg (10) (1979) 1438). In the Wittig reaction (Wittig reacti〇n), in the presence of a room temperature (2〇1〇〇. 〇 and a base such as butyl lithium) in an aprotic solvent (eg tetrahydrofuran, monothyl sulfoxide or The toluene-substituted estroxone derivative of the general formula (IV) is converted into toluene by using, for example, a fluorenyltriphenylsulfonium halide for 8 hours (1 to 24 hours). Form 17_exomethylene steroid of formula (ν) (process step b)).

In step c), it is possible to use, for example, meta-perbenzoic acid in an aprotic solvent (for example, dioxane) at room temperature (〇_1〇〇χ) for a period of 4 hours. The cyclic external olefin of formula (V) is converted to the 丨7_ spiro epoxide of formula (VI) within 8 hours). The crude product (VI) of this reaction cannot be stored stably and can be purified in 148586.doc -25-201103547 and in step d) at 10t: (0-80 ° C) in an aprotic solvent (eg tetrahydrogen) In the case of ruthenium or fluorene benzene, for example, lithium aluminum hydride is immediately converted into 17β-alkyl-anthracene-3,].7α-diol of the general formula (VII) in a period of 2 hours (丨24 hours). The group "_ch2-R20" at position 17 represents the group R"·'.

In step e), the protected or free Ι7β-alkyl-estrene-3,17α-diol of the formula (VII) can be converted, as desired, to the halogenated estradiol of the formula (VIII), for example by Add a halogenating agent (eg 2,3,4,5) in a polar aprotic solvent (eg dimethylamine) for 22 hours (4-48 hours) at room temperature (〇-l〇〇 °C) 6,6-hexa-2,4-cyclohexadien-1-one).

In step f), it may be carried out in an organic acid (for example, oxalic acid) or a fluoride (for example, tetrabutylfluoride) at room temperature (〇_ 1 〇〇c) and in a polar solvent (for example, water or ethanol). 12 hours (4-48 hours) to remove any protection at the 3-position 148586.doc -26- 201103547 base, convert the protected or free halogenated estradiol of formula (VIII) as needed Forming a female diol derivative of the formula (IX), for example, by using a polar aprotic solvent (for example, pyridine or dimethylformamide) at room temperature (0-100 ° C) for 12 hours. A deuteration or etherification agent (for example, decyl anhydride, hydrazine or alkyl halide) is added for a period of time (4-48 hours). R ir

0

In step g), at room temperature (20-100 t:) in a polar. aprotic solvent (eg dimethyl ketoamine) '(if appropriate) in inorganic tests (eg carbonated steel) and iodide salts (eg In the presence of sodium iodide, an amino-derivative derivative of the formula (I) is converted to the formula (I) by using an amine structural unit of the formula (xv) for 8 hours (4-48 hours). amine. R,

General method for the preparation of amine structural units of formula (XV):

Y r\一* Ε N—χ 蛾 mothing effect: 148586.doc ·27· (XV) 201103547 hctt, e (X) Έ (XI) In step h) 'can be used, for example, at room temperature ( 20-100. 〇) The addition of the general formula (χ) alcohol to the reaction solution of triphenylphosphine and iodine in the sputum in 1 hour (0.25-8 hours) to convert it into a general formula (χΙ ) Iodide. (XI)

Ph3Pi T: (x«l) In step 1), the iodide of the formula (χι) can be added to a suspension of triphenylphosphine contained in an aprotic polar solvent such as acetonitrile, and The formula (χ(1) Wittig salt was obtained by stirring at a boiling point (40-10 (TC) for 8 hours (2-24 hours).

PG

N-X (XIII)

Ph3pi-_Y

E (XII) j)

PG

N-X V,

E (Xiv) In the step j), the formula (xm) aldehyde or ketone can be added dropwise to the formula containing the aprotic solvent (for example, tetrahydrocarbamate) (χτυ维蒂希 salt and In the reaction solution (for example, sodium hexadecyl-sodium azide), heat to room temperature (〇8〇c&gt;c) and stir at this temperature for another hour (〇5-10 hours). 4 (Converted to olefin under the rc(78 3(rc) conversion to the general formula (XIV) as needed. R6 R5\ k) R5 R6 —X PG (XIV)

E irx

-Y (XV)

E can be used in step k) in a polar solvent (eg aqueous ethanol solution) in the presence of a large 148586.doc •28-201103547 gas pressure (1-20 bar) and a hydrogenation catalyst (eg platinum oxide) Hydrogen (X-V) is used to hydrogenate the protected flue-cured tobacco of the formula (XJV) for 1 hour (0.5-8 hours) and, if appropriate, deprotected, for example, using an acid such as hydrochloric acid. An amine of the formula (XV). The method for preparing the alcohol of the formula (X): H〇r 0 I m&gt;., + 卜日_- Η〇Λ-ε ~ Η〇, γ, ε (XVI) (XVII) (XVIII) (8) can be (for example In step I), in the presence of sodium bicarbonate and sodium dithionate, at -10 ° C (-30-30 ° C) in a polar aprotic solvent (eg acetonitrile), using formula (XVII) The iodide converts an alkynyl alcohol of the formula (XVI) wherein -y, (CH2)2_ represents -Y-) to a vinyl iodide of the formula (XVIII). In step m), hydrogen can be used at room temperature (〇_8〇»c) at atmospheric pressure (1-20 bar) in the presence of a hydrogenation catalyst (for example palladium supported on activated carbon). The vinyl iodide of the formula (?νιπ) is hydrogenated to the alcohol of the formula (X) in an hour (0.5-8 hours).制. Example 1 of the preparation method of the compound according to the present invention [5·(11β-fluoro_3,17α_dihydroxy_17-methylethylidene^3,5^0)triene_7α_yl)pentyl](methyl) (8,8,9,9,9-pentafluoroindenyl)amine

1.1 Process for the preparation of intermediates 148586.doc 29· 201103547 1·1·1 3-(Tertiary butyl decyl decyloxy)-7α-(5-chloropentyl)-up_Fluorine·1,3 , 5(10)-triene-17-one, 3.81 g of imidazole was added to 15.7 g of 7α-(5-chloropentyl)-11β-fluoro-3-trans-yl-17β-methyl female at room temperature Cui-1,3,5(10)-Sannong-17-酉同[WO 99/33855,CAS: 204138-84-1] contained in 160 ml of dioxane in a solution of 'cooling the mixture to 1 g ° C, 8.44 g of a third butyl dimethyl sylvestre base gas was added in a small amount each time, and the mixture was incubated at room temperature for 3 hours. In order to complete the reaction, the phases were separated with a saturated aqueous sodium hydrogen carbonate solution (40 ml) and 80 ml of water, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. This gave 21 g of crude 3-(t-butyldidecyldecyloxy)-7ct-(5-pentylpentyl)-11?-fluoroestrazine-triene-17-one. H-NMR: 400 MHz, CDC13, 6 = 7.16 (d, 1H), 6.67 (d(br), 1H), 6.58 (s(br), 1H), 5.58 (d, 1H), 3.51 (t, 2H) ), 0.98 (s, 9H), 0.91 (s, 3H), 0.19 (s, 6H). 1.1.2 3-(Tertiary dimethyl dimethyl decyloxy) 7α (5-pentyl pentyl); l ip_fluoro-17-methylene ketone-usqo)·triene in the next 'will 36 ml butyl The lithium solution (25 μ solution contained in hexane) was added to the solution of the layer of methyl bromide in the tetrahydroquinone in a period of 10 knives for 4 liters, and the mixture was placed in the chamber. Stir at room temperature for 2 minutes and then heat to 7 (rc, which will be contained in 28 〇ml of tetrahydrofuran. ιο·ΐ4 g 3-(Tertiary butyl dimethyl decyloxy pentyl oxime · fluoro A solution of the female 1,3,5(1〇)_triene_17-ketone was added dropwise over a period of 8 minutes and the mixture was stirred at a bath temperature of 95 hours for completion of the reaction with ice cooling. 160 ml of water were added dropwise, the phases were separated, and the aqueous phase was taken with ethyl acetate. 148586.doc 201103547. The combined organic phase was washed with saturated sodium carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. A crude product. The product was stirred with 1 mL of hexanes at 4 (c), decansed and dried under reduced pressure, and repeated four times. This gave 11.6 g of purified crude product 3- (t-butyl bis Methyl decyloxy 7α_(5_Vetyl)-11β-fluoro-17-methylene estradiol. H-NMR: 300 MHz, CDC13, δ= 7.18 (d, 1H), 6.67 (m, 1H), 6.57 ( s(br), 1H), 5.57 (d(br), 1H), 4.67 (m, 2H), 3.51 (t, 2H), 0.97 (s, 9H), 0.19 (s, 6H). 1·3 3 -(t-butyldimethylmethylalkoxy)_7α (5 gas pentyl ΐβ· chaos-(17R)-spiro-[female retention_; ι,3,5(10)_three rare _17,2, epoxy B烧] At room temperature, 3.05 g of gas was added to a little amount of 5.32 g of 3_(t-butyldimethyl oxalate) in 55 m of chloroform. a solution of -7α-(5-chloropentyl)_Up_fluoro_17•arylene-seuratriene, and the mixture was mixed for 4 hours. To complete the reaction, 5 〇ml of saturated sodium bicarbonate solution and 5 〇 ml of methyl tert-butyl ether, the phases were separated, the aqueous phase was extracted with decyl-tert-butyl hydrazine and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. 3_(Tertiary butyl-fluorenyloxy)-7α-(5-chloropentyl)-lip_K17R)_ snail·[Female 甾 1,3,5(10)-triene _17,2, -Ethylene oxide] H-NMR: 300 MHz, CDC13, 6=7.16 (d} ι ), 6.67 (m, 1H), 6.57 (S(br), 1H), 5.57 (d, 1H), 3.51 (t, 2H), 3 22 (s, ih), 1.02 (s(br), 3H) , 0.98 (s, 12H), 0.19 (s, 6H). 1·1·4 3-(Tertiary butyl decyl decyloxy) _7a (s chloropentyl) ιιρ· 148586.doc • 31 · 201103547 Fluorine 17β-indolyl-i, 3, 5 ( L〇)·Triene_ΐ7α-alcohol '5.27 g of 3-(t-butyldidecyldecyloxy)-7α·(5-chloropentyl) contained in 20 ml of tetrahydrofuran at 10 ° C a second solution of -11β-fluoro-(17R)-spiro-[female__ 1,3,5(10)-triene-17,2,-oxirane] is added dropwise to the hydrogenation of 2 Μ The solution was smeared (5.03 ml) and the mixture was stirred at room temperature for 2 hours. To complete the reaction, add 8 ml of acetone and 70 ml of citric acid solution, dilute the mixture with 80 ml of ethyl acetate, separate the phases, extract the aqueous phase with ethyl acetate and rinse the combined organic phase with sodium chloride solution in sodium sulphate. It was dried, concentrated under reduced pressure and purified using hexane/ethyl acetate. This gave 2_75 g of pure 3-(t-butyldidecyldecyloxy)·7α_(5-valylpentyl)-1 1β-fluoro-17β-methylestrazine-1,3,5(10)- Triene-17α-alcohol. H-NMR: 300 MHz, CDC13, δ = 7.17 (d, 1H), 6.65 (m, 1H), 6.57 (s(br), 1H), 5.52 (d, 1H), 3.51 (t, 2H), 1.26 (d, 3H), 0.98 (s, 9H), 0.91 (d, 3H), 0.19 (s, 6H). 1.1.5 methyl-(8,8,9,9,9-pentafluoroindenyl)amine is compressed at -2 〇C to 4.0 g of decylamine to be contained in i〇m丨 pure tetrahydrofuran. 2.9 g of 8,8,9,9,9-pentafluorodecyltoluenesulfonate [Protocol 99/33 855, page 20 'CAS: 228570-38-5] in solution and the mixture under pressure The vessel was stirred at room temperature overnight. At _2. (: The pressure vessel is vented and allowed to warm to room temperature' to evaporate excess guanamine. The reaction solution is dissolved in dioxane, rinsed with water, dried over magnesium sulfate and concentrated under reduced pressure. This gave 1.58 g of crude methyl (8,8,9,9,9-pentafluoroindenyl)amine as a crude product. H-NMR: 300 MHz, CDC13, 5 = 2.60 (t, 2H) ( 2.47 (s, 3H), 1.94-2.14 (m, 2H), 1.57-1.68 (d, 2H), 1.48-1.56 (m, 2H), 148586.doc 32· 201103547 1.34-1.46 (m, 6H) 1.2 Preparation of the final product Add 0.22 g of sodium, 〇63 g of hardened sodium and usliu,^,9,9·pentafluoroindenyl) oxime to i 3 g 3_(6) contained in 6.29 ml of dimethylformamide a solution of a third butyl dimethyl decyloxy "slightly pentyl group" ηβ fluoro-17β- fluorenyl f 1 '3'5(10)-triene 17α-alcohol, and the mixture is scratched After stirring for 5 hours, to complete the reaction, the mixture was diluted with 1 ml of ethyl acetate and washed with water and sodium hydrogen hydride solution, and the organic phase was dried over sulphuric acid, and the mixture was taken and evaporated under reduced pressure. Dissolve in 9 44...ethanol, add 〇.73 potassium telluride and 〇.2ml water and mix the mixture at room temperature The mixture was stirred for 14 hours, and then the mixture was concentrated under reduced pressure and chromatographed on EtOAc EtOAc EtOAc EtOAc. Estradiol-1,3,5(1〇)-triene_7α-yl)pentyl](indenyl)(8,8,9,9,9-pentafluoroindenyl)amine H-NMR: 600 MHz, CDC13, δ= 7.18 (d, 1H), 6.63 (m, lH) 6.52 (s(br),1H), 5.60 (d,1H), 2.21 (s, 3H), I.% (s,3h) )' 0.88 (d,3H) ° , Example 2 lip-fluoro-17P-methyl_7„-[5_[(2"_2_(7,7,8,8,8-pentafluorooctyl)_1〇 Pyridyl]indolyl-1,3,5(10)-triene-3,17α-diol

2.1 The method of making intermediates 148586.doc -33· 201103547 2·1·1 (Η)-2,7,7,8,8,5 IL octyl)&quot;Biropyridine

a) 6,6,7,7,7-pentafluoro _4-iodeng·4_ dilute _ι_ alcohol

F F

I F F was added at _12C to 507 g of pentafluoroiodoethane to a solution of 150 g of 4-pentynol in 1.5 L of acetonitrile and 1-14 L of water. Subsequently, a mixture of 15 〇 g of sodium hydrogencarbonate and 294 g of sodium dithionite (purity: 85%) was added, and the mixture was stirred at -10 to 0 ° C for a few hours. The reaction was checked by tlc and then the reaction mixture was added to water and extracted with ethyl acetate, and the extract was washed with saturated sodium sulfate solution and dried over sodium sulfate. After filtration, the extract was carefully concentrated on a rotary evaporator at 1 Torr. This gave a crude product (650 g) of 6,6,7,7,7-pentafluoro-4-iodohept-4-en-1-ol. b) 6,6,7,7,7-pentafluoroheptan-1-ol CAS [344452-11-5]

F F H〇 eight

FF Π 8 g palladium-1 -carbon was added to 650 g of crude 6,6,7,7,7-pentafluoro-4- contained in 3 l of ethyl acetate and 500 ml of triethylamine at room temperature. In the solution of iodohept-4-en-1-ol - and then the mixture was hydrogenated at atmospheric pressure under a hydrogen atmosphere, and the progress of the reaction was monitored by 1H-NMR. After filtration and washing with a solvent of ethyl acetate. The organic phase was washed with water, 1% hydrochloric acid and a saturated sodium carbonate solution. After drying with sodium sulfate and carefully concentrating the solvent to 50 mbar, 'distilled 148586.doc •34·201103547 at 65 ° C in oil pump vacuum (0.5 mbar) to obtain 6,6,7,7,7 - pentafluoroheptan-1-ol (235 L). H-NMR: 400 MHz, CDC13, δ = 3.66 (t, 2H), 2.03 (m, 2H), 1.40-1.70 (m, 7H). c) 1,1,1,2,2-five--7-eheng

At room temperature, 61.56 g of iodine was added with cooling to a solution of 64_25 g of triphenylphosphine contained in 5 〇〇 ml: hexane, and the mixture was stirred for 15 minutes. Then, a solution of 50 g of 6,6,7,7,7-pentafluoroheptan-1-ol contained in 6 〇 ml of dichlorohydrazine was added dropwise over 1 hour, and the mixture was stirred for another hour. The mixture was added to water and extracted with di-methane. The organic phase was washed with saturated sodium sulfate solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue was digested with 300 ml of hexane and the obtained hexane phase was distilled at 1 mbar, which afforded pent. H-NMR: 300 MHz, CDC13, δ = 3.20 (t, 2H), 2.03 (m, 2H), 1.86 (m, 2H), 1.43-1.69 (m, 4H). d) moth (6,6,7,7,7-pentafluoroheptyl) three stupid scales

313 g of 1,1,1,2,2-pentafluoro-7-iodoheptane was added to a suspension of 260 g of triphenylphosphine contained in 1.26 L of acetonitrile, and the mixture was heated under reflux 18 hour. The solvent was concentrated and the product was crystallized twice from &lt;RTI ID=0.0&gt;&gt; This gave a white powder (6,6,7,7J_penta-heptyl)triphenyl scale (567 g). ι H-NMR: 300 MHz, CDC13, δ = 7.66-7.91 (m, 15 H)j 3.76 (m, 2H), 1.50-2.10 (m, 8H). e) (8)-2_[(ζ)-7,7,8'8,8·pentafluoro-i-alkenylpyrrolidin-ucarboxylic acid tert-butyl ester

FF At -40 ° C, 738 ml of sodium hexadecyldioxane (1 Μ solution in tetrahydrofuran) was added over 10 minutes to 468.38 g of iodinated in 3 8 L of tetrahydrofuran (6, 6,7,7,7-pentafluoroheptyl;) a solution of triphenylphosphine, and the mixture was allowed to stand at this temperature for 2 hours. Then, a solution of 147 g of (3S)-tert-butyl 3-pyridyl-1-pyrrolidinecarboxylate in 85 〇 (6) was added over a period of 5 minutes, and the mixture was stirred at -4 CTC for 1 hour, and allowed to warm to room temperature. Stir for another hour. After the addition of 2.5 L of hexane, the mixture was concentrated to 1/3 of its original volume to add a third butyl fluorenyl group and allowed to precipitate. The mixture was then filtered, the filter cake was rinsed with butyl methyl ether and the filtrate was concentrated to dry. Flash chromatography (hexane/ethyl acetate) on silica gel gave (3)-2-[(2)-7,7,8,8,8-pentafluorooct-1-yl). Bilo bite __ tert-butyl formate (155.7 g). H-NMR: 300 MHz, CDC13, δ= 5.33 (m, 2H), 4.47 (br. s, 1 H), 3.37 (m, 2H), 1.41 (s, 9H) » f) (R)-2- (7,7,8,8,8-pentafluorooctyl)pyrrolidine-1-carboxylic acid tert-butyl ester 148586.doc •36- 201103547

6_19 g of platinum oxide was added to 61.9 g (S)_2_(7,7,8,8,8-pentafluorooctane) in 水中4 sterol and 3 〇〇W water at room temperature. . Bilo bites a solution of formic acid terpene vinegar and hydrogenates the mixture at atmospheric pressure until hydrogen absorption has been completed. After filtration through a layer of Celite, the filtrate was concentrated and evaporated in ethyl acetate. The solution was filtered through a PTFE filter and then evaporated to dryness. The obtained crude product (R)-2-(7,7,8,8,8-pentafluorooctyl)n is more directly used in the next step than the tributyl bromo-pyridinium citrate (59.6 g). . H-NMR: 300 MHz, CDC13, δ = 3.71 (br. s, 1H), 3.21-3.43 (m, 2H), 1_44 (s, 9H).

Add 35 ml of hydrochloric acid (37% strength) to 35 g of (R)-2_(7,7,8,8,8-pentafluorooctane) contained in 636 ^ 1,4-dioxane at room temperature (b) pyrrolidine g) (only) -2- (7,7,8,8,8-pentafluorooctyl) "better than guanidine dibutyl sulfonate / in solution" and then the mixture Heat at 5 1 for 1 hour. Next, the mixture was concentrated and added to dichlorohydrazine, and the mixture was washed twice with a saturated sodium hydrogencarbonate solvent and water, dried over magnesium sulfate and concentrated, and purified by kugelrohr (boiling point: 110_125. (:, 1) The product is purified by torr). This gives (R) 2-(7,7,8,8,8-pentafluorooctyl). Specific to 21 g). 148586.doc •37- 201103547 H-NMR: 400 MHz, CDC13, 6= 3.00 (ddd, 1 H), 2.92 (m, 1 H), 2.81 (ddd, 1 H), 2.00 (m, 2H), 1.87 (m, 1H), 1.52-1.80 (m, 6H), 1.28-1.51 (m, 8H), 1.21 (m, 1H). 2.2 The final product was prepared in a similar manner to Step 1.2 of Example 1, 1 · 1 g of 3-(t-butyldidecyldecyloxy)-7α-(5-apentyl)-11β-fluoro-17β-methyl Estradiol - l,3,5(10)-triene-3,l7α-diol and 860 mg of (R)-2-(7,7,8,8,8-pentafluorooctyl)pyrrolidine (as amine After the rapid chromatography, 11β-fluoro-17β-mercapto-7cx-[5-[(2R)-2-(7,7,8,8,8-pentafluorooctyl)-1-) was produced. Bilpyridyl]pentyl]estrone-1,3,5(10)-triene-3,17α-diol (772 mg). H-NMR: 400 MHz, CDC13, δ = 7.19 (d, 1H), 6.65 (m, 1H), 6.55 (s(br), 1H), 5.60 (d, 1H), 3.14 (m, 1H), 2.91 (m, 1H), 2.54 (m, 1H), 1.26 (s, 3H), 0.88 (d, 3H). Example 3 lip-fluoro-17P-mercapto-7a-[5-[(2R)-2-(6,6,7,7,7-pentafluoroheptyl)-1-l-pyrrolidyl]pentyl] Estradiol-1,3,5(10)-triene-3,17〇1-diol

3.1 Preparation of intermediates 3.1.1 (R)-2-(6,6,7,7,7-pentafluoroheptyl)pyrrolidine

a) 5,5,6,6,6-pentafluoro _3_iodohexyl _3_en-1-ol 148586.doc -38- 201103547

F F

FF is similar to the method described in Example 2 · 1.1 a) sleeve, using 280 g 3-butyn-1-ol and 1136 g pentafluoroethyl 缂 令 又 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 The crude product of pentafluoro-3-iodohex-3-en-1-ol (1205 g) can be directly used in the next step. b) 5,5,6,6,6- Pentafluorohexyl-ΐ·Xue (y^ir ^ (ZK 6074973, CAS [58556-45-9])

F F

FF is similar to the method described in Example 2.1.1 b), using 5195 g 5,5,M,6_pentafluoro-3-E-hex-3- -3- alcohol-1 to obtain 5,5,6,M_five Fluenol (223 g). H-NMR. 300 MHz, CDC13, δ = 3.69 (t, 2H), 2.06 (m, 2H), 1.54-1.77 (m, 5H). c) 1,1,1,2,2-five-6-Ethylene

F F

FF is similar to the method described in Example 2.1.1 c), using 1,223 g of 5,5,6,6,6-pentafluoro-hexan-1-ol to obtain 1,1,1,2,2-pentafluoroiodine Hexane (223 g). H-NMR: 300 MHz, CDC13, δ = 3.20 (t, 2H), 1.85-2.15 (m, 4H), 1.66-1.79 (m, 2H). d) Iodinated (5,5,6,6,6-pentafluorohexyl)triphenyl scale

-39- 148586.doc 201103547 t, using 334 g pentafluorohexyl) triphenyl scale (671 similar to the method described in Example 2.1.1 d) to obtain hardening of pentafluoro-6-Ethone (5,5, 6,6,6_j g). H-NMR: 300 MHz, CDC13, δ = δ = 7.65-7.92 (m, 15 Η), 3.88 (m, 2 Η), 1.73-2.22 (m, 6 Η). e) (S)-2-[(Z)-6,6,7,7,7-pentafluoroheptenyl]n-pyrrolidine a-carboxylic acid tert-butyl ester

Similar to the method described in Example 2.1.1 e), (8)-2 was obtained using 3 1 8 g moth (5,5,6,6,6-pentafluorohexyl)triphenyl scale (671 g). - [〇6,6,7,7,7 -5 said hept-1-yield]β is compared with each of η-1-pyruic acid tert-butyl vinegar (132.7 g). H-NMR: 300 MHz, CDC13, δ= 5.29-5.49 (m, 2H), 4.52 (m,1H),3_44 (m,2H), 2.28 (m,2H),1·46 (s,9H) ° f) (only) 2-(6,6,7,7,7-pentafluoroheptyl)pyrrolidine-1-carboxylic acid tert-butyl ester

3.72 (br. s, H-NMR: 300 MHz, CDCh, (m, 2H), 1.44 (s, 9H). 3.72 (br. s, 1H), 3.23-3.39 148586.doc -40- 201103547 g) ( 1〇-2-(6,6,7,7,7-pentafluoroheptyl).Byrrolidine

Similar to the method described in Example 2.1.1 g), using 20.5 g of (R)-2-(6,6,7,7,7-pentafluoroheptyl)pyrrolidine-l-carboxylic acid tert-butyl ester (R)-2-(6,6,7,7,7-pentafluoroheptyl). Birolidine (13 g). H-NMR: 400 MHz, CDC13, δ = 4.09 (br s, 1H), 3.00 (m, 2H), 1.61-1.94 (m, 5H), 1.21-1.59 (m, 9H). 3.2 The final product was prepared in a similar manner to step 1.2 of Example 1, 1.1 g of 3-(t-butyldidecyldecyloxy)-7α-(5-apentyl)-11β-fluoro-17β-methylestrone - l,3,5(10)-triene-3,17 (x-diol and 820 mg(R)-2-(7,7,8,8,8-pentafluoroheptyl)pyrrolidine (as amine After the rapid chromatography, 11β-fluoro-17β-mercapto-7〇1-[5-[(211)-2-(6,6,7,7,7-pentafluoroheptyl)-1-) was produced. H-NMR: 400 MHz, CDC13, δ = 7.18 (d, 1H) ), 6.63 (m, 1H), 6.53 (s(br), 1H), 5.60 (d, 1H), 3.16 (m, 1H), 2.90 (m, 1H), 2.54 (m, 1H), 1.26 (s , 3H), 0.88 (d, 3H). Example 4 4-Gas-lip-Fluoro-17β-indenyl_7α-[5-[indenyl (8,8,9,9,9-pentafluoroindenyl) Amino]pentyl]-estrone-1,3,5(10)-triene-3,17α-diol

148586.doc -41 - 201103547 4·1 Preparation of intermediates 411 3_(Tertiary butyl decyl decyloxy)-4-chloro-7α-(5-chloropentyl)-11β-fluoro-17P-曱Alkaloid-i,3,5(10)-triene-17α-ol

505 mg of 2,3,4,5,6,6-hexa-2,4-cyclohexadien-1-one was added to 732 mg of 3- contained in 9 ml of dimethyl decylamine under a nitrogen atmosphere. (Third butyl decyl decyloxy)-7α-(5-aepentyl)-11β-fluoro-17β-indolyl-1,3,5(1〇)-tris-ΐ7α-ol The solution was stirred and allowed to mix at room temperature for 22 hours. An additional 126 mg of 2,3,4,5,6,6-hexa-2,4-cyclohexadien-1·one was added and a final 126 mg of this material was added after 7 hours. The reaction mixture was stirred for an additional 56 hours and then concentrated, and the crude product was chromatographed on EtOAc (hexane/ethyl acetate) 444 mg of 3-(t-butyl-decyl-decyloxy) -7α-(5-chloropentyl)-1 1β-fluoro-17β-mercapto-istra-1,3,5(1〇)-triene-17α-ol H-NMR: 400 MHz, CDC13, δ = 7.12 (d, 1H), 6.75 (m, 1H), 5-59 (d, 1H), 3.51 (t, 2H), 3.06 (d, 1H), 1.26 (s, 3H), 1.03 (s, 9H) ), 0.87 (d, 3H), 0.23 (s, 3H), 0.22 (s, 3H). 4.2 The final product was prepared in a similar manner to that in Example 1. ,2,428 mg 3-(t-butyldimethyl) Oxalyloxy)-4-chloro-7(4-(pentyl)-11β-fluoro-ΐ7β-methyl-anthracene-^3,5(10)-triene_17α_ alcohol and 284 mg (8, 8,9,9,9·pentafluoroanthryl)methylamine 148586.doc -42· 201103547 (as an amine) after flash chromatography to produce 4-gas-11β-fluoro-17β-methyl-7α_[5_ [A (8,8,9,9,9-pentafluoroindenyl)amino]pentyl]estrone-1,3,5(10)-trioxin-3,17α-diol (176 mg). -NMR: 400 MHz, CDC13, δ = 7.20 (d, IH), 6.89 (m, 13⁄4) 5.59 (d, 1H), 3.00 (d3 1H), 2.18 (s, 3H), 1.26 (s, 3H), 〇.8? (d, 3H) Example 5 4-Bromo-lip-fluoro-l7p-mercapto_7α_[5_[mercapto (8,8,9,9,9-pentafluoroindenyl)amino]pentyl]estrone-1,3, 5(10)-triene-3,17&lt;*-diol

5.1 Preparation of intermediates 5·1·1 7α-(5-chloropentyl hup·fluoro·17ρ·methylestrene-3,17α-diol

2.13 g of potassium fluoride and 0.55 ml of water were continuously added to 3.2 g of 3-(t-butyldimethylsilyloxy)_7α_(5-chloropentyl)_llp_fluoro_17β-曱 contained in 27 ml of ethanol. A solution of creed H, 3, 5 (1 〇)_triene _17α-alcohol, and the mixture was stirred at room temperature for 18 hours. The solvent was concentrated, and then the residue was dissolved in ethyl acetate and washed twice with water and sodium chloride solution. Filtration was carried out on a 1485S6.doc -43- 201103547 phase and the solvent was removed on a rotary evaporator, and then flash chromatography (hexane/ethyl acetate) on silica gel, which gave 7α_(5_apentyl)_u PF_17β-methylestrone-1,3,5(1〇)-triene·3,17α-diol (2 74 g). H-NMR·· 400 MHz, CDC13, δ= 7.20 (d,1H), 6.67 (m,1H), 6.57 (s (br.)5 1H), 5.60 (d, 1H), 4.71 (s, 1H) , 3.51 (t, 2H), 2.92 (dd, 1H), 2.71 (d, 1H), 2.54 (dd, 1H), 0.88 (d, 3H) 〇 5.1.2 4-bromo-7a-(5-qi Radyl-17?-methylestrone Lww)-triene-3,17α-diol

Br

HO Add a solution of L17 g N-bromosuccinimide contained in 167 ml of air to 2.5 g of 7α-(5·chloropentyl)_110 contained in 278 ml of gas at 〇 °C a solution of -fluoro-170-methyl-anthracene-1,3,5(1?)-triene_3,17?..diol, and then the mixture was stirred at this temperature for 3 minutes. The mixture was then slowly warmed to room temperature and stirred for an additional 3 minutes. The reaction mixture was concentrated and the residue was taken from ethyl acetate. Rapid chromatography on the tannin extract (Hangyuan/ethyl acetate) to obtain 4-bromo-7-(5-apentyl)_πβ_fluoro-170-methyl-anthracene-1,3,5(1〇) - Triene-3,17〇1-diol (1.86§). H-NMR: 400 MHz, CDC13j δ = 7.25 (dj 1H), 6.91 (m5 1H), 5.60 (d, 1H), 5.56 (s, 1H), 3.52 (t, 2H), 2.95 (d, 1H), 1.26 (s, 3H), 0.87 (d, 3H). 5.2 Preparation of the final product 148586.doc -44 - 201103547 Add 77.1 mg of sodium carbonate, 218.1 mg of sodium hydride and 270 mg of (8,8,9,9,9-five murmur) methylamine at room temperature Up to 355 mg of 4-bromo-7α-(5-aepentyl)-1 ΐβ·fluoro-ΐ7β-mercapto-indenyl-1,3,5(10)- contained in 2.18 ml of dimethylamine In a solution of triene-3,17α-diol. The mixture was then mixed at 85 ° c for 5 hours. After removing the solvent, the residue was dissolved in ethyl acetate and the solution was washed with water and a half-saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered, and the solvent was removed on a rotary evaporator. Flash chromatography (amine phase; hexane/ethyl acetate) on Shixi gum gave 4-bromo-11β-accord 17β-mercapto-7α-[5-[methyl(8,8,9, 9,9-pentafluoroindenyl)amino]pentyl]estrone 4,3,5(10)-triene-3,17α-diol (228 mg) 'recrystallized from diethyl ether . H-NMR: 400 MHz, CDC13, δ= 7.24 (d, 1H), 6.90 (d, 1H) 5.59 (d, 1H), 2.96 (d, 1H), 2.18 (s, 3H), 1.26 (s, 3H ), 0.87 (d, 3H). Example 6 4-&gt; Odor-11-Fluoro-17--Methyl-7 (*-[5_[(2 ft)-2-(7,7,8,8,8-pentafluorooctyl)) 1·pyrrolidinyl]pentyl]estrone-1,3,5(10)-triene-3,17α-diol

Similar to step 5.2 of Example 5, 223 mg 4-bromo-7α-(5-chloroindolyl)-fluoro-17β-methylisine-1,3,5(10)-triene-3,17α_ Alcohol and 187 mg of (R)-2-(7,7,8,8,8-pentafluorooctyl)pyrrolidine (as amine) (compound 2丨丨) in flash chromatography (amine phase; hexane/acetic acid) Ethyl ester) after the formation of 4_演_丨丨β_say Πβ-mercapto 8,8,8-pentafluorooctyl)_丨_pyrrole bite] 148586.doc -45- 201103547 pentyl] female 甾-1 , 3,5(10)-triene-3,17α-diol (250 mg). H-NMR: 400 MHz, CDC13, δ=7.24 (d, 1H), 6.90 (d, 1H) 5.60 (d, 1H), 3.13 (m, 1H), 2.96 (d, 1 H), 1.26 (s, 3H), 0.86 (d, 3H). Example 7 4-Gas-lip-Fluoro-17β-methyl-7〇1-[5-[(21^)-2-(7,7,8,8,8-pentafluorooctyl)-1·pyrrole Pyridyl]pentyl]estrone-1,3,5(10)-triene-3,17α-diol

7.1.1 Preparation of intermediates 7.1.1 4-Gas-7α-(5-aepentyl)-lip-fluoro·17ρ_ 曱 甾 甾 usqo). Tris-3,17 α-diol

164 mg of potassium fluoride and 42 μl of water were continuously added to 262 mg of 3_(t-butyldimethylsilyloxy)_4_gas (5-pentylpentyl) contained in 8 ml of ethanol at room temperature. -UP-fluoro-Ηβ-mercapto-relative-1,3,5(10)-triene_17α-alcohol, and the mixture was stirred at room temperature for 24 hours. The solvent was concentrated and the residue dissolved in ethyl acetate and washed with water. After filtering the organic phase and removing the solvent on a rotary evaporator, followed by flash chromatography (hexane/ethyl acetate) on silica gel to give 4-chloro-7-(5-chloropentyl) 17β-mercapto-androgens-1, 3 5 (1〇)·triene _317α diol (94 mg). 148586.doc •46· 201103547 H-NMR: 400 MHz, CDC13, δ= 7.21 (d,1H),6-90 (d,1H), 5.60 (d,1H),5.55 (s (br.),1H ), 3.52 (t, 2H), 2.98 (d, 1H), 1.26 (s, 3H), 0.87 (d, 3H). 7.2 The final product was prepared in a similar manner to the procedure of Example 5 5.2 '206 mg 4-gas-7α-(5·valyl)_11β-fluoro-17β-indolyl 甾_1,3,5(1〇)_ Repeated flash chromatography with triene_3,17α-diol and 209 mg of (R)-2_(7,7,8,8,8-pentafluorooctyl)pyrrolidine (as amine) (compound 2丨丨) (Amine phase followed by amine phase; hexane/ethyl acetate) followed by 4_chloro-11β-fluoro-1邛_methyl-7a-[5-[(2R)_2_(7,7,8,8,8 _ pentafluorooctyl)_ 1-. Bilpyridyl]pentyl] erion-1,3,5(10)-triene_3,17a-diol (165 mg). H-NMR: 400 MHz, CDC13, δ = 7.20 (d, 1H), 6.90 (d, 1H), 5.60 (d, 1H), 3.12 (m, 1H), 2.99 (d, 1H), 1.26 (s, 3H)} 0.876 (s (br·), 3H). Example 8 4_Bromo-lip-fluoro-17p-mercapto-7a-[5-[(2R)-2-(6,6,7,7,7-pentafluoroheptyl)- 1-pyrrolidinyl]pentyl ]1,3,5(1〇)_triene·3,17α-diol

11β-fluoro-17β-methylisine-1,3,5(ι〇)·triene_3,17α-diol and 178 mg (R)-2-(7,7,8,8,8- Pentafluoroheptyl"pyrrolidine (as an amine) after flash chromatography (gelatin: hexane/ethyl acetate) to form anal bromide 氟 氟 氟 氟 曱 曱 曱 - - 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 148 [(2R)-2-(6,6,7,7,7-pentafluoroheptyl)-1-0-pyrrolidyl]pentyl]estrone-1,3,5(10)-triene- 3,17α-diol (287 mg) H-NMR: 400 MHz, CDC13, δ= 7.24 (d, 1H), 6.90 (d, 1H), 5.60 (d, 1H), 3.12 (m, 1H), 2.96 (d, 1H), 1.26 (s, 3H), 0.86 (d, 3H). Example 9 4-chloro-lip-fluoro-17p-methyl-7 (*-[5-[(21〇-2-) (6,6,7,7,7-pentafluoroheptyl)_1-pyrrolidinyl-pentyl]estrone-1,3,5(10)-triene-3,17α-diol

9.1 Method for the preparation of intermediates 9.1.1 4-Gas-7α-(5-chloropentyl)-11β-fluoro-17Ρ-indenyl 甾_1,3,5(1〇) Tris-3,17α-II alcohol

In addition to the procedure according to step 7.1 of Example 7, 239 mg of 2,3,4,5,6,6-hexa-2,4-cyclohexadien-1-one can be obtained under a nitrogen atmosphere. Add to 325 mg (5-gaspentyl)_ubufluoro-17β-indenyl-1,3,5(1〇)-triene_3,17α- contained in 6 ml of dimethylformamide 4_Chloro_7α_(5_apentyl)_nbufluoro·17ρ_methylisine_1,3,5(10)-triene_ was prepared by stirring in a solution of diol for 24 hours at room temperature. 3, ΐ7α-diol. An additional 12 mg of 2,3,4,5,6,6-hexa-2,4-cyclohexadien-1-one was subsequently added. After stirring for an additional 56 hours of I48586.doc -48-201103547, the reaction mixture was added to water and extracted with ethyl acetate. After drying and concentrating the organic phase, followed by flash chromatography (hexane/ethyl acetate) on silica gel to obtain 4-chloro-7α-(5-chloropentyl)-11β-fluoro-ΐ7β-methyl female _ 1,3,5(1〇)-triene_3,17α-diol (240 mg). H-NMR: 400 MHz, CDC13, as described in 7.1 _ 1 . The final product was prepared in a similar manner to the step 5.2 of Example 5, 24 〇 mg 4 _ _ 7α-(5- pentyl)-110-fluoro-1%-indolyl-1,3,5 ( 1〇)-tris-3,17〇1-diol and 238 111§ (R)-2-(7,7,8,8,8-pentafluoroheptyl)pyrrolidine (as an amine) are repeated Rapid chromatography (after the oxime is the amine phase; hexane / ethyl acetate) to form 4-gas-11β-fluoro-17β-mercapto-7a-[5-[(2R)-2-(6,6,7 , 7,7-pentafluoroheptyl)-1-. Bilobidyl]pentyl]estrone-1,3,5(10)-triene-3,17a-diol (205 mg). H-NMR: 400 MHz, CDC13, δ = 7.20 (d, 1H), 6.89 (d, 1H), 5.60 (d, 1H), 3.14 (m, 1H), 2.99 (d, 1H), 1.26 (s, 3H), 0.87 (d, 3H) 〇 Example 10 2,4_Dichloro-IIP-fluoro-17β-mercapto-7a_[5-[(2R)-2-(7,7,8,8,8-five Fluorooctyl)-1-pyrrolidinyl]indolyl]Essence-^5(10)-triene-3,17a-diol

10.1 Method for the preparation of intermediates 1〇·1·1 7a_(5-chloropentyl)-2,4-digas-lip-fluoro-17P-methyl-anthracene-1,3,5 (1 〇) ·Two dilute -3,17 a -diol 148586.doc •49- 201103547

In addition to the desired pure target structure, the gasification described in step 4.41 of Example 4 also obtained a small amount of 3-(t-butyldimethyl oxa oxooxy)-4- after flash chromatography. Gas-7α-(5-aepentyl)-11β-fluoro-17β-mercapto-androgens-1,3'5(10)-triene_17〇1-alcohol and 3-(t-butyldimethyl) a mixture of decyloxy)_7〇1_(5-pentyl)-2,4-dioxa·ιΐβ_fluoro·17β-methylision-1,3,5(10)-triene-17α-alcohol It was subjected to de-spinning according to the method described in Example 711. Flash chromatography (hexane/ethyl acetate) on silica gel to obtain 7α-(5-pentylpentyl)-2,4-digas _110_fluoro_170_ fluorenyl--13,500)-5 « ene- 3,17α-diol (76 mg). </ RTI> <RTI 1.26 (s, 3H), 0.86 (s, 3H) 最终i〇·2 The final product is prepared in a similar manner to step 5.2 of Example 5, 76 mg 7α-(5-apentyl)-2,4-digas-110 - defeat -170-曱基女甾-1,3,5 (1〇三三稀_3,17〇1_diol and 65111§ (R)-2-(7,7,8,8,8- Pentafluorooctyl)pyrrolidine (as an amine) (Compound 2丨丨) was obtained after flash chromatography (Shihic; hexane/ethyl acetate), preparative HPLC and removal of traces of citric acid using sodium bicarbonate solution. 2,4_Dichloro_UpFluorine_17Busyl-7a-[5-[(2R)-2-(7,7,8,8,8-pentafluorooctyl)-1-indolyl]penta Estradiol-1,3,5(10)-triene_3,17a-diol (16 mg) H-NMR: 400 MHz, CDC13, δ= 7.27 (s, 1H), 5.54 (d, 1H), 148586.doc •50- 201103547 3.13 (m,1H), 2.98 (d,1H), 1.26 (s,3H), 0.86 (d,3H). Β·Control of l7〇i-alkyl compounds Cl: 11β-fluoro-17α-methyl-7α-[5-[methyl(8,8,9,9,9-pentafluoroanthryl)amino]pentyl]estrone-1,3,5 ( 10)-Triene-3,17β-diol CAS [536975-64-1] ΟΗ

Adding 12.75 g of mercapto-(8,8,9,9,9-pentafluoroindenyl)amine and 5.47 g of sodium carbonate to 19,5 g of 7α-(5- contained in 200 ml of pure dinonylfurfural a solution of bromopentyl)·11β-fluoro-17α-indolyl-l,3,5(10)-triene-3,17β-diol (w〇2003/045972, page 27, 2.2a) in. The mixture was stirred at 8 ° C for 5·5 hours. After removing the solvent, the residue was dissolved in ethyl acetate. The mixture was washed with water and a half-saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and filtered, and the solvent was removed on a rotary evaporator. Flash chromatography on the gelatin (amine phase; hexane/ethyl acetate) gave 丨丨 氟 丨 丨 ^ -7 -7 -7α-[5-[曱基 (8,8,9,9,9 -pentafluoroanthryl)amino]pentyl;|male retention _ 1,3,5(1〇)_triterpene-3,17β-diol (14.5 g)' recrystallized from diethyl ether H-NMR: 300 MHz, CDC13, δ=7.16 (d, 1H), 6.64 (d, 1H), 6-54 (d, 1H), 5.56 (d, 1H), 2.90 (d, 1H), 2.69 (d, 1H), 2.40-2.34 (m, 4H), 2.25 (s, 3H), 1.06 (d, 3H). C2: lip-fluoro-17a-mercapto-7a-[5-[(2R)-2-(7,7,8,8,8-pentafluorooctyl) small 0 to 148586.doc •51 · 201103547 Pyridyl]pentyl]estrone_1,3,5(1〇)_triene_3,17β·diol

Add 3.0 g of (2R)-2-(7,7,8,8,8-pentafluorooctyl)pyrrolidine, 2. 〇丨g sodium carbonate and 2.53 g of sodium iodide to the pure diterpene contained in 45 mi 3.45 g of 7α-(5-apentylmethylestrone-ene-3,17β-diol in a solution of carbamide. The mixture was then stirred at 1 〇〇&lt;&gt;c for $hour. After removing the solvent, the residue was dissolved in ethyl acetate, the mixture was washed with water and a half-saturated sodium hydrogen carbonate solution, dried over sodium sulfate and filtered and evaporated on a rotary evaporator. Flash chromatography (amine phase; hexane/ethyl acetate to obtain i! fluoro_17α_mercapto_7α-[5-[methyl(8,8,9,9,9-pentafluoroantimony))) ] amyl]isan-1,3,5(1〇)-dilute-3,1 7β-monool (4·5 g), which is recrystallized from a diethyl bond. H-NMR: 600 MHz , CDC13, δ = 7.17 (d, 1H), 6.66 (d, 1H), 6.56 (d, 1H), 5.56 (d, 1H), 2.89 (d, 1H), 2.71 (d, lH), l〇6 (d, 3H). C3:

Lip-fluoro-17a-methyl_7〇1_[5_[(2]^_2_(6,6,7,7,7-pentafluoroheptyl)-1-pyrrolidinyl]pentyl]estrene _3,17p diol 0H

148586.doc -52· 201103547 Add 11.83 g of (2艮)2-(6,6,7,7,7-pentafluoroheptyl)pyrrolidine, 2 6§ sodium carbonate and 7.33 g of sodium iodide to Wg 7α-(5-aepentyl)-ΐ ΐβ_fluoro_ι7α_methyl female 甾13,5(1〇)_tris 3,17β-diol in 50 ml of pure dimercaptodecylamine In solution. The mixture was then stirred at 8 ° C for a hour. After the solvent was removed, the residue was dissolved in ethyl acetate, and the mixture was washed with water and a half-saturated sodium hydrogen carbonate solution, dried over sodium sulfate and filtered, and the solvent was removed on a rotary evaporator. Flash chromatography (amine phase; hexane/ethyl acetate) on silica gel to obtain 110_Fluorine_17〇1•曱基_7α_[5_[曱基(7,7,8,8,8-pentafluoro) Indenyl)amino]pentyl]estrone_1,3,5(1o)_triene·3,17β-diol (9.84 g) was recrystallized from diethyl ether. H-NMR: 600 MHz, CDC13, δ = 7.15 (d, 1H), 6.61 (d, 1H) 6.51 (d, 1H), 5.56 (d, 1H), 2.88 (d, 1H), 2.72 (d, 1H) ), l.〇5 (d, 3H). C. Qualitative analysis c.l Qualitative analysis test description C.1.1 Metabolic stability:

The metabolic stability of the substance of the type 5 was measured by culturing in a suspension having human liver microsomes (regulated protein content of 0.5 mg/mi) at a concentration of 〇 · 3 μΜ. The culture volume is 3_〇3 ml', which firstly injects 2.4 ml of particles contained in phosphate buffer (sodium phosphate buffer, 1〇〇1111^(]^112?〇0 H20+Na2HP04χ2H20)) at pH 7.4. Body suspension by adding 0.6 ml of a cofactor mixture (from 12 mg NADP, 3 IU glucose 6-phosphate dehydrogenase, 14.6 mg glucose 6-phosphate, and sodium silicate at pH 7,4) 4.9 mg of MgCl2 in the flush was activated. The analysis was started by adding 30 pL 148586.doc • 53· 201103547 test substance stock, wherein the stock solution was such that the solvent concentration was DMSO &lt; 0.2% and methanol &lt; 1% during the culture. The incubation was carried out for 60 minutes at a culture temperature of 37 ° C during which the microparticle system was maintained in a homogeneous suspension by continuous agitation (Tec Control Shaker RS 485 at 3 Torr). At 6 different time points (2, 8, 16, 30, 45 and 60 minutes 4) 'In each case, remove 2500 μΐ aliquots and immediately add to the same volume of ice-cold methanol and cap . The sample was frozen overnight at _2 〇〇 c and then centrifuged at 3,000 rpm for 15 minutes, after which 1 μ μl of the clarified supernatant was removed to determine the concentration. Analysis using an Agilent 1200 HPLC system in combination with LCMS/MS detection. The half-life of the test substance in the above microsomal culture mixture was determined by decreasing the concentration over time, which was further used to calculate the "intrinsic clearance rate" (maximum liver of the metabolic clearance test substance) Microsome speed) This "inherent clearance rate" can be used together with different physiological parameters to assess the maximum metabolic clearance rate in humans. The above mentioned principle can only represent the stage i metabolic reaction (generally Zytochrom Redox reaction of P450 enzyme or flavin monooxygenase, and hydrolysis reaction of esterase and prolylase). Physiological parameters: human liver blood flow: 1.3 l / kg / h; specific liver weight (per kg body weight): 21 g / kg; microsome protein content: 40 mg / gR. In addition, assume that (1) the reabsorption rate of the test substance in humans is 100%, and (Η) the metabolic clearance rate estimated by the initial calculation method, and the maximum oral bioavailability (Fmax) 评估 formula and brief description: Appearance Intrinsic CL [in ml/(min*mg protein)]: Indicates the clearance constant kel of the test substance in the culture mixture (in terms of Xenopus): 148586.doc -54 - 201103547 Microsomal protein content (40 mg/ Ml). Intrinsic CL [in l(h*kg)]: The maximum capacity of the liver (microsome) to metabolize the test substance, unless the liver blood flow is a limiting factor (kel* liver weight) / the proportion of liver in the culture (microsome content °° uniformly stirred blood CL [in l/(h*kg)]: evaluated blood clearance rate (metabolized via stage 1) · (QH* intrinsic CL) / (QH + intrinsic CL). : Fmax [in °/°]: Maximum bioavailability of the test substance after oral administration: (1_ uniformly stirred blood CL/QH)*100. C. 1.2 Bioavailability The intragastric bioavailability of the test substance is determined in a female waking dog having a body weight of at least 5 kg and at most 12 kg. For this purpose, the test substance is administered in a dissolved form with a phase capacity compatible solubilizing agent such as PEG400 and/or ethanol for intravenous infusion and intragastric administration. Intravenous administration: The test substance was infused at a low dose of 0.2-1 mg/kg for 15 minutes. At 5 minutes, 1 minute, 15 minutes (for example, before the end of the infusion), 20 minutes, 30 minutes '45 minutes, 1 hour, 2 hours 4 hours, 6 hours, 8 hours, 24 hours ( Blood samples from approximately 丨_丨5 m丨 were drawn based on the start of the infusion. Blood samples were stored without shaking in a lithium/heparin tube (from Monovettes® from Sarstedt) and centrifuged at 3000 rpm for 15 minutes. A 100 μΐ specific sample was removed from the supernatant (blood water) and sanitized by the addition of 4 μ μΐ of cold ACN. The precipitated sample was cold-branched at -20 ° C overnight and then centrifuged at 3 rpm for 15 minutes, after which 15 〇 μΐ of the supernatant was removed to determine the concentration. Analysis was performed using an Agilent 1200 HPLC system in conjunction with LCMS/MS detection. Calculation of PK parameters (via ρκ calculation software, eg winN〇nLin®): 148586.doc -55- 201103547 Plasma CL: total bacterial clearance of test substance (in L/kg/h); blood CL: test substance Total blood clearance (in L/kg/h), where (blood CL = plasma CL*Cp/Cb); Vss: stable volume in the stable state (in L/kg); T1/2: in The half-life of the specified interval (here the end point T1/2, in h); AUCnorm: the area under the time curve of the blood concentration from the time point of induration to infinity divided by the dose (in kg*L/h) AUC(0-tn)norm : integrated area below the plasma concentration curve from time 0 to the last time point at which measurable plasma concentration is present divided by dose (in kg*L/h); Cmax: in plasma test Maximum concentration of substance (in g/L); CmaX, n〇rm · Maximum concentration of test substance in plasma divided by dose (in kg/L); Cb/Cp: ratio of blood: plasma concentration distribution. Administration by intragastric administration: At a low dose of 1-2 mg/kg, the test substance is administered to the unfed female dog by intragastric administration via a gastric tube. At the time points of 15 minutes, 3 minutes, 45 minutes, 1 h '2 h, 4 h, 6 h, 8 h, 24 h (based on the start of the infusion), about 1-1.5 ml of blood was removed. Blood samples were stored without shaking in a lithium-heparin official (Monovettes® from Sarstedt) and centrifuged at 3000 rpm for 15 minutes. An aliquot of 1 μl was taken from the supernatant (plasma water) and precipitated by the addition of 400 μM cold ACN. The precipitated sample was frozen overnight at _2 〇 t: and then centrifuged at 3 000 rpm for 15 minutes, after which 15 〇 μ丨 of the clarified supernatant was removed to determine the concentration. Analysis was performed using an Agilent 1200 HPLC system in conjunction with LCMS/MS detection. Calculation of pk parameters (software via PK, eg WinN〇nLin&lt;g)): AUCnorm: blood plasma concentration time curve from zero time point to infinity 148586.doc -56 - 201103547 area underneath divided by dose (in kg *L/h count); AUC(0-tn)norm: the integrated area below the plasma concentration time curve from the zero time point to the final time point at which the measurable plasma concentration is present divided by the dose (in kg*L/h) Clnax: the maximum concentration of the test substance in the blood table (in pg/L); Cmax, norm: the maximum concentration of the test substance in the blood test divided by the dose (in kg/l); T1/2: in the designation Half-life within the time interval (here the endpoint T1/2, in h); Fobs%. Observed oral bioavailability, which is the eUC (0-tn)n〇rm divided by the dose Ie AUC (0-tn) norm after administration. Tmax : The time point at which the maximum concentration of the test substance in the plasma is measured. C · 2 Results Table 2 shows the results of the qualitative analysis of PK (C1-3: direct analog, that is, the difference is only the stereoisomerism at position 17). Compound [Example] Fmax (microsome) Fobs (canine) "%1 1 39 a uosv L 7 uj C1 9 1 LI 2 8 2 36 13 C2 9 2 3 40 13 C3 8 3 1 4 39 - 丄丄 5 -- --- 55 6 34 ----- 7 47 ' 14 8 48 9 42 10 34 Table 2 148586.doc -57- 201103547 The compound according to the invention having a 17β-group is superior to the direct analogue because it After administration by intragastric administration, it has increased metabolic stability in human microsomes and increased bioavailability in dogs. 148586.doc •58·

Claims (1)

201103547 VII. Shenqing patent scope: 1. A compound of formula (I) And its enantiomers and diastereomers, salts thereof, salts of the formulations; solvates and solvates wherein the wrist represents fluorine or chlorine, which is attached to the (tetra) trisex backbone; and R1 R2 and R4 independently of each other represent hydrogen, fluorine, gas odor, and R represents hydrogen or C^C4_alkyl or CVC4-calcinyl, and R represents hydrogen or CVC4-alkyl or alkane, R17 represents If desired, single- or multi-gasified ^--alkyl, C2_C4. alkenyl or C2-C4-alkynyl, wherein Rl7'-0 and R&quot;·' are attached at 17α_ position and 17M vertical respectively To the leucotriene skeleton; and U represents a linear or branched chain, a c2_Ci3_enyl or C2-Cn-extension group, or a group AB, wherein the A is attached to the estradiol On the skeleton, attached to the benzylidene group on the estradiene skeleton via _c; H2_, phenyl or 148586.doc 201103547 via the alkyl group attached to the female triterpene 牟 ^ Zhu Shangzhi C〗 -C3-alkylene: phenyl, and B linear or branched ρ r chain Cl-C| 3-alkyl, C2-C13-alkenyl or C2-C13-exetylene, and Among them AD can also be via oxygen atoms (4), VX R5 R6 generation a methylene or -c(〇)- group and a representative bond or a Ci-ον extension group and a hydrogen or a heart-alkyl group, a c2_c4_thin group or a C2_C4_ block group represent a hydrogen or a group even ^ c (q) _r7, wherein the towel r7 represents ammonia or a linear or branched chain non-fluorinated or at least partially fluorinated C1_C6_alkyl C^C6.alkenyl or C2-C0-alkynyl, which may be via a hydroxy group or Multiple substitutions, or R and R together with X and the nitrogen atom of the side chain, form a core or a 6-shell heterocyclyl ring which may have other heteroatoms other than the nitrogen atom of the side chain and/or may contain a carbonyl group, representing C5- C8 - an extended alkyl group, representing C]-C4_perfluoroalkyl or a phenyl group substituted by halogen or Cf3 mono- to penta. 2. A salt of a compound of the formula and its enantiomers and diastereomers, salts, solvates and solvates thereof, wherein Hal represents fluorine and RR and R systems independently represent hydrogen and gas. Or 9 and r3 represent hydrogen, fluorenyl or ethenyl, and ^ ' represents nitrogen or C1-C3 -alkyl, and R6 represents hydrogen or -CHz-R7, wherein R7 represents hydrogen or fluorenyl or 148586.doc The base of 201103547, or R and R together with the nitrogen atom of the side chain, form a 5- to yano-based ring which may have other heteroatoms in addition to the nitrogen atom of the side chain and/or may comprise a carbonyl group, and RRUV represents hydrogen, a methyl or ethyl fluorenyl group, and represents a fluorenyl group, an ethynyl group or a trifluoromethyl group, and represents a butyl group, a pentyl group, a hexyl group or a heptyl group, and represents an anthracene group, and x represents a bond or an anthracene. And γ represent a bond or a c5-c7-alkylene group, and 3. 4. E represents _C2F5, -(:3F7, -c4f9 or represents a tris-ylphenyl group. The compound of claim 1 or 2 and a salt thereof enantiomers and diastereomers, salts, solvates and solvates thereof, wherein r1 represents hydrogen and r2 represents hydrogen or And R represents a hydrogen, a chlorine or a bromine. The compound of any one of the above items 1 to 3, and the enantiomers and diastereomers thereof, salts, solvates and solvates thereof, wherein R3 represents a hydrogen. The compound of any one of claims 1 to 4, and the enantiomers and diastereomers thereof, salts, solvates and solvates thereof, wherein Hal represents fluorine. The compound of any one of claims 1 to 5, and the enantiomers and diastereomers thereof, salts, solvates and solvates thereof, wherein 148586.doc 201103547 represents hydrogen and R6 represents A The group or R and R are formed together with the nitrogen atom of the side chain. Each of the compounds of any one of claims 1 to 6 and its enantiomers and diastereomers, a salt of a salt, a solvate or a solvate, wherein R17' represents hydrogen and Ri7&quot; represents a fluorenyl group. 8. The compound of any one of the claims and its enantiomers and diastereomers, a salt thereof, a solvate or a solvate thereof, wherein U represents a n-butyl group. And its enantiomers and diastereomers, salts, solvates and solvates thereof, wherein V represents a methylene group. 1〇·如叻目 [to any of 9 a salt of the compound and its enantiomers and diastereomers, salts, solvates and solvates thereof, wherein X represents a bond. 11. A compound according to any one of claims 1 to 10 and a pair thereof Salts of the enantiomers and diastereomers, salts, solvates and solvates thereof, wherein Y represents a pentyl group or a hexyl group. The compound of any one of the items 1 to 11 and its enantiomers and diastereomers, salts, solvates and solvates thereof, and E represents -c2p5. a salt of a compound of the formula (I) and its enantiomers and diastereomers, salts, solvates and solvates thereof, wherein R1 represents hydrogen, and R2 represents hydrogen or gas, and 148586.doc 201103547 R represents Hydrogen, gas or bromine, and R3 represents hydrogen, and Hal represents fluorine, and r5 represents hydrogen and R6 represents methyl, or R and R together with the nitrogen atom of the side chain form a pyrrolidine ring, and Rl7 represents hydrogen, and Rl7&quot; Represents a fluorenyl group, and U represents a n-butyl group, and V represents an anthracene group, and x represents a bond, and γ represents a pentylene group or a hexanyl group, and E represents a —C 2 F 5 group. 14. 15. 16. 17. An intermediate of formula (IX), Wherein R1, R2, r3, R, H. R17·, Rl7&quot;, ΜV have the definitions as defined in any one of claims 1 to 13 and LG represents a sulfonate group or a yl group. Female. A compound according to any one of items 1 to 13, which is for use as a medicament. The use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment of an estrogen-dependent disease. A side drug formulation comprising the compound of any one of claims 3 to 3. 148586.doc 201103547 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the characteristics that can best display the invention. Chemical formula: 148586.doc